The Brain and its Vasculature represents the continuation of a 39 year study of the vasculature and metabolism of the human brain and their relationship to brain function in health and disease. This competing renewal carries forward these long standing interests. Three new themes serve to motivate and integrate the work of the three proposed projects. First, functionally-relevant intrinsic brain activity as opposed to evoked activity accounts for the vast majority of the brain's huge energy budget. Second, an important albeit small fraction of the metabolism associated with this ongoing intrinsic activity is aerobic glycolysis. Available data indicate that aerobic glycolysis may be linked to glutamatergic signaling. Third, apparently driven by this ongoing aerobic glycolysis, spontaneous fluctuations in the fMRI BOLD imaging signal are present in the quiet, resting awake state. Their study provides a detailed picture of the dynamic organization of the brain's intrinsic activity. Finally, Alzheimer's disease (AD) is of particular interest in this context because the areas of brain exhibiting the earliest changes in metabolism and intrinsic functional connectivity in AD have the highest levels of aerobic glycolysis and spontaneous BOLD activity in young normals. In Project 1 we will continue a detailed exploration of the relationship between mechanisms that link amount of aerobic glycolysis to the regulation of brain circulation. Work to date indicates a unique role for the NADH/NAD* system in setting the gain of the vasculature to match the amount of glycolysis and, hence, function. In Project 2 we will undertake a detailed study of the spontaneous fluctuations in the fMRI BOLD imaging signal, determining its relationship to evoked activity and its effect on involuntary behavior. We will also test the hypothesis that functional reorganization of the brain consequent to blindness (now a well-established phenomenon) will be manifest as intrinsic functional connectivity differences between sighted vs. blind participants. In Project 3 we will examine the effect of Alzheimer's disease (AD) on the regulation of the cerebral vasculature with particular attention to the loss of autoregulation. Together, Projects 1, 2 and 3 will examine the relationship of the spontaneous BOLD fluctuations to ongoing aerobic glycolysis on a regional basis in young and older normal adults. And, finally, Projects 2 and 3 will study how the relationship between ongoing aerobic glycolysis and BOLD fluctuations changes in AD and determine whether these changes correlate with beta amyloid deposition and loss of blood flow autoregulation.